The Dual Role of HIF Hydroxylase PHD3 in Cancer Cell Survival
Rantanen, Krista (2012-10-12)
The Dual Role of HIF Hydroxylase PHD3 in Cancer Cell Survival
Rantanen, Krista
(12.10.2012)
Annales Universitatis Turkuensis D 1033 Turun yliopisto
Julkaisun pysyvä osoite on:
https://urn.fi/URN:ISBN:978-951-29-5133-8
https://urn.fi/URN:ISBN:978-951-29-5133-8
Kuvaus
Siirretty Doriasta
Tiivistelmä
Most advanced tumours face periods of reduced oxygen availability i.e. hypoxia.
During these periods tumour cells undergo adaptive changes enabling their survival
under adverse conditions. In cancer hypoxia-induced cellular changes cause tumour
progression, hinder cancer treatment and are indicative of poor prognosis.
Within cells the main regulator of hypoxic responses is the hypoxia-inducible factor
(HIF). HIF governs the expression of over a hundred hypoxia-inducible genes that
regulate a number of cellular functions such as angiogenesis, glucose metabolism and
cell migration. Therefore the activity of HIF must be tightly governed. HIF is regulated
by a family of prolyl hydroxylase enzymes, PHDs, which mark HIF for destruction in
normoxia. Under hypoxic conditions PHDs lose much of their enzymatic activity as they
need molecular oxygen as a cofactor. Out of the three PHDs (PHD1, 2 and 3) PHD2 has
been considered to be the main HIF-1 regulator in normoxic conditions. PHD3 on the
other hand shows the most robust induction in response to oxygen deprivation and it has
been implied as the main HIF-1 regulator under prolonged hypoxia.
SQSTM1/p62 (p62) is an adaptor protein that functions through its binding motifs to
bring together proteins in order to regulate signal transduction. In non-stressed situations
p62 levels are kept low but its expression has been reported to be upregulated in many
cancers. It has a definitive role as an autophagy receptor and as such it serves a key
function in cancer cell survival decisions.
In my thesis work I evaluated the significance of PHD3 in cancer cell and tumour biology.
My results revealed that PHD3 has a dual role in cancer cell fate. First, I demonstrated that
PHD3 forms subcellular protein aggregates in oxygenated carcinoma cells and that this
aggregation promotes apoptosis induction in a subset of cancer cells. In these aggregates
an adaptor protein SQSTM1/p62 interacts with PHD3 and in so doing regulates PHD3
expression. SQSTM1/p62 expression is needed to keep PHD3 levels low in normoxic
conditions. Its levels rapidly decrease in response to hypoxia allowing PHD3 protein
levels to be upregulated and the protein to be diffusely expressed throughout the cell. The
interaction between PHD3 and SQSTM1/p62 limits the ability of PHD3 to function on its
hydroxylation target protein HIF-1alpha. Second, the results indicate that when PHD3 is
upregulated under hypoxia it protects cancer cells by allowing cell cycle to proceed from
G1 to S-phase. My data demonstrates that PHD3 may either cause cell death or protect the
cells depending on its expression pattern and the oxygen availability of tumours.
During these periods tumour cells undergo adaptive changes enabling their survival
under adverse conditions. In cancer hypoxia-induced cellular changes cause tumour
progression, hinder cancer treatment and are indicative of poor prognosis.
Within cells the main regulator of hypoxic responses is the hypoxia-inducible factor
(HIF). HIF governs the expression of over a hundred hypoxia-inducible genes that
regulate a number of cellular functions such as angiogenesis, glucose metabolism and
cell migration. Therefore the activity of HIF must be tightly governed. HIF is regulated
by a family of prolyl hydroxylase enzymes, PHDs, which mark HIF for destruction in
normoxia. Under hypoxic conditions PHDs lose much of their enzymatic activity as they
need molecular oxygen as a cofactor. Out of the three PHDs (PHD1, 2 and 3) PHD2 has
been considered to be the main HIF-1 regulator in normoxic conditions. PHD3 on the
other hand shows the most robust induction in response to oxygen deprivation and it has
been implied as the main HIF-1 regulator under prolonged hypoxia.
SQSTM1/p62 (p62) is an adaptor protein that functions through its binding motifs to
bring together proteins in order to regulate signal transduction. In non-stressed situations
p62 levels are kept low but its expression has been reported to be upregulated in many
cancers. It has a definitive role as an autophagy receptor and as such it serves a key
function in cancer cell survival decisions.
In my thesis work I evaluated the significance of PHD3 in cancer cell and tumour biology.
My results revealed that PHD3 has a dual role in cancer cell fate. First, I demonstrated that
PHD3 forms subcellular protein aggregates in oxygenated carcinoma cells and that this
aggregation promotes apoptosis induction in a subset of cancer cells. In these aggregates
an adaptor protein SQSTM1/p62 interacts with PHD3 and in so doing regulates PHD3
expression. SQSTM1/p62 expression is needed to keep PHD3 levels low in normoxic
conditions. Its levels rapidly decrease in response to hypoxia allowing PHD3 protein
levels to be upregulated and the protein to be diffusely expressed throughout the cell. The
interaction between PHD3 and SQSTM1/p62 limits the ability of PHD3 to function on its
hydroxylation target protein HIF-1alpha. Second, the results indicate that when PHD3 is
upregulated under hypoxia it protects cancer cells by allowing cell cycle to proceed from
G1 to S-phase. My data demonstrates that PHD3 may either cause cell death or protect the
cells depending on its expression pattern and the oxygen availability of tumours.
Kokoelmat
- Väitöskirjat [2866]